(a) Field of the Invention
The invention relates to novel regulators of plasminogen activation and their use for regulating cell migration and treating cancer. Furthermore, the present invention relates to novel pharmaceutical compositions form regulating cell migration and treating cancer.
(b) Description of the Prior Art
Melanotransferrin (p97) possesses a high level of homology (37-39%) with human serum transferrin, human lactoferrin and chicken transferrin. It is a glycosylated protein that reversibly binds iron and was first found at high levels in malignant melanoma cells. Two forms of p97 have been reported, one of which is bound to cell membranes by a glycosylphosphatidylinositol anchor while the other form is both soluble and actively secreted. The exact physiological role of either membrane-bound p97 or secreted p97 is largely unexplored.
In the early 1980s, p97 was found to be expressed in much larger amounts in neoplastic cells and fetal tissues than in normal tissues. More recently, it was reported that p97 mRNA is widespread in normal human tissues. p97 is also expressed in reactive microglia associated with amyloid plaques in Alzheimers disease. Normal serum contains very low levels of p97, which were reported to increase by 5- to 6-fold in patients with Alzheimer's disease.
It was previously demonstrated that recombinant human melanotransferrin (p97) is transported at high rate into the brain using both an in vitro model of the blood brain barrier (BBB) and in situ mouse brain perfusion (Demeule M, et al., 2002 J Neurochem 83:924-933). It was also shown that p97 transcytosis might involve the low-density lipoprotein related protein (LRP). This receptor is also known to mediate the internalization of the urokinase:plasminogen activator inhibitor:urokinase receptor complex (uPA:PAI-1:uPAR). Briefly, single-chain proenzyme-uPA is activated upon binding to its cell surface receptor uPAR; which is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. After its activation, uPA (which catalyzes the conversion of plasminogen to plasmin) is quickly inhibited by the plasminogen activator inhibitor type-1 (PAI-1). The inactive uPA:PAI-1 complex binds to uPAR and then is rapidly internalized by LRP. The uPA:PAI-1 complex is degraded in lysosomes whereas the uPAR is recycled at the cell surface. Other LRP ligands include pro-uPA, PAI-1, receptor-associated protein (RAP) and a diverse spectrum of structurally unrelated proteins.
Heart disease has topped the list of killer diseases every year but one since 1900. (The exception was 1918, when an influenza epidemic killed more than 450,000 Americans.) Stroke is the third leading cause of death in the United States, following cancer. Much of the progress is due to the development of effective medicines to control blood pressure and cholesterol, according to officials of the National Heart, Lung and Blood Institute. But, experts warn, the war against heart disease and stroke is not yet won. Every 33 seconds, an American dies of either heart disease or stroke. Nearly 62 million Americans have one or more types of cardiovascular disease, and these diseases cost our society more than $350 billion a year.
Two strategies are presently used to restore the flow after thrombosis: 1) clot dissolution with administration of plasminogen activators and 2) clot permeation by surgical intervention. The tissue-type plasminogen activator (tPA) and its conventional substrate plasminogen, are key players involve in fibrinolysis. Currently, tPA is used as a stroke therapy, however, its associated adverse effects might limit its efficiency.
It would be highly desirable to be provided with novel regulators of plasminogen activation and their use for regulating cell migration and treating cancer.
It would also be highly desirable to be provided with novel pharmaceutical compositions form regulating cell migration and treating cancer.
It would be highly desirable to be provided with a new treatment for thromboembolic disorders such as venous or arterial thrombosis, thrombophlebitis, pulmonary and cerebral embolism, thrombotic microangiopathy and intravascular clotting. Some of these disorders will lead for example in heart and cerebral strokes.
It would be also desirable to be provided with a new method for increasing fibrinolysis or for preventing angiogenesis.